SAN DIEGO -- Zack Greinke reached a big career milestone on Tuesday night at Petco Park, but he also saw a personal streak end in untimely fashion.

The D-backs’ right-hander recorded his 2,500th career strikeout when he fanned Franmil Reyes in the fourth. Two innings later, Greinke’s streak of 178 batters faced without allowing a home run ended when Eric Hosmer delivered a two-run shot that sent the Padres to a 3-2 victory.

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Greinke, 35, is the 37th pitcher to reach 2,500 strikeouts and the fifth active, joining CC Sabathia (3,013), Justin Verlander (2,795), Max Scherzer (2,536) and Felix Hernandez (2,501).

By the time his seven-inning, five-strikeout outing was over, Greinke was up to 2,502 strikeouts, ahead of Hernandez and tied with Hall of Famer Christy Mathewson for 35th all-time.

“I think we all need to sit back and appreciate what that means and who we have throwing for us every fifth day,” D-backs manager Torey Lovullo said. “He’s a very special, special pitcher.”

Early solo homers by Eduardo Escobar and John Ryan Murphy staked Greinke to a 2-0 lead. But the D-backs' bats were shut down after the fifth, and for the second straight game, the Padres deflated a stellar performance by a D-backs starting pitcher with a big homer in the sixth inning.

Hosmer went the opposite way with a first-pitch, 88.9 mph Greinke fastball that brought in Manny Machado and capped a three-run inning, putting the Padres ahead, 3-2. On Monday, Reyes’ two-run shot put Luke Weaver on the wrong end of a 2-1 duel.

“We have a very, very good offensive team,” Lovullo said. “We have a lot of capabilities, but we’re putting a lot of pressure on our pitchers. We’re not really building innings the way we can. We’re not having the big innings like we were. But that capability is in there. We’re going to keep pounding away.”

Greinke (6-2) took a loss for the first time since Opening Day, despite taking a one-hit shutout into the sixth inning. He was stung by the offensive inconsistency of D-backs, who have lost 11 of their last 16 games and fallen to 25-24 in a second-place tie with the Padres in the National League West. Arizona has scored five runs over their last three games and lost four in a row.

“As an offense, we know what we’re capable of,” Murphy said. “We can explode at any time. Credit to the pitching staff for keeping us in games. That’s not always easy to do.”

Said Greinke: “You just keep trying to make pitches and not get frustrated if you give up a couple runs.”

Greinke had not allowed a homer since Padres rookie Fernando Tatis Jr. connected against him in the fifth inning on April 14 at Chase Field. He has allowed nine homers this season -- four on Opening Day against the Dodgers and five in three games vs. the Padres.

“He's a guy you don't want to fall behind,” Hosmer said. “We were aggressive early, and we didn't miss those pitches.”

Greinke, in his 16th big league season, has 615 strikeouts in four seasons with the D-backs. He had 931 with the Royals, 323 with the Brewers, 78 with the Angels and 555 with the Dodgers. His top strikeout victim is Carlos Pena, with 21 in 42 at-bats.

Given the turn of events in the sixth inning, he wasn’t in a reflective mood about his milestone.

“I haven’t thought about it at all,” Greinke said. “I didn’t even know that it happened.”